1. Field of the Invention
The present invention relates generally to reverse-turn mimetics, including inhibitors of cell adhesion-mediated disease, central nervous system disorder, and several other disorders as well as to a chemical library of reverse-turn mimetics.
2. Description of the Related Art
Reverse-turns comprise one of three classes of protein secondary structure and display three (gamma-turn), four (beta-turns), or more (loops) amino acid side chains in a fixed spatial relationship to each other. Turns have proven important in molecular recognition events (Rose et al., Advances in Protein Chemistry 37:1-109, 1985) and have engendered a burgeoning field of research into small molecule mimetics of them (Hanessian et al., Tetrahedron 53:12789-12854, 1997). Many mimetics have either been external turn-mimetics which do not allow for the display of all the physiologically relevant side-chains (Freidinger et al., Science 210:656-8, 1980) or small, conformationally mobile cyclic peptide derivatives (Viles et al., Eur. J. Biochem. 242:352-62, 1996). However, non-peptide compounds have been developed which closely mimic the secondary structure of reverse-turns found in biologically active proteins or peptides. For example, U.S. Pat. Nos. 5,475,085, 5,670,155 and 5,672,681 to Kahn and published PCT WO94/03494 to Kahn all disclose conformationally constrained, non-peptidic compounds which mimic the three-dimensional structure of reverse-turns. More recently, U.S. Pat. No. 5,929,237 to Kahn, published PCT WO97/15577 to Kahn, published PCT WO98/49168 to Kahn et al., U.S. Pat. No. 6,013,458 to Kahn et al., U.S. Pat. No. 6,184,223 to Kahn et al. and published PCT WO01/16135A2 to Stasiak et al. disclosed additional, highly constrained bicyclic heterocycles as reverse-turn mimetics.
In view of the important biological role played by the reverse-turn, there is a need in the art for compounds that can mimic the reverse-turn structure. There is also a need in the art for methods of making stable reverse-turn mimetics, as well as the use of such stabilized structures to effect or modify biological recognition events that involve reverse-turn structures. The present invention fulfills these needs and provides further related advantages.
Cell adhesion is critical to the viability of living organisms. Adhesion holds multicellular tissues together and directs embryonic development. It plays important roles in wound healing, eradication of infection and blood coagulation. Integrins are a family of cell surface proteins intimately involved in all of these functions, and have been found in nearly every type of human cell except red blood cells. Abnormalities in integrin function contribute to a variety of disorders including inflammatory diseases, heart attack, stroke, and cancer. Integrins consist of heterodimers of α and β subunits, non-covalently bound to each other. At least 15 different α and 9 different β subunits are known. Integrin α4β1 mediates cell adhesion primarily through binding to either vascular cell adhesion molecule-1 (VCAM-1) or an alternatively spliced variant of fibronectin containing the type III connecting segment (IIICS). Low molecular weight peptidyl derivatives have been produced as competitive inhibitors of α4β1 and one has been shown to inhibit allergic airway responses in sheep (Lin et al., J. Med. Chem. 42:920-34, 1999).
Cyclic peptides and derivatives thereof that adopt reverse-turn conformations have proven to be inhibitors of VCAM-1 binding to α4β1 (WO 96/00581; WO 96/06108; Doyle et al., Int. J. Pept. Protein Res. 47:427-36, 1996). In addition, a number of potent and selective (versus α5β1) cyclic peptide-based inhibitors have been discovered (Jackson et al., J. Med. Chem. 40:3359-68, 1997). In addition, while α4 integrins appear to be down-regulated in carcinomas such as cervical and prostate, they appear to be up-regulated in metastatic melanoma (Sanders et al., Cancer Invest. 16:329-44, 1998), suggesting that inhibitors of α4β1 and α4β7 may be useful as anticancer agents. Several non-peptidyl beta-turn mimetics have also been reported to bind α4β1 with IC50s in the low micromolar range (Souers et al., Bioorg. Med. Chem. Lett. 8:2297-302, 1998). Numerous phenylalanine and tyrosine derivatives have also been disclosed as inhibitors of α4β1 (WO 99/06390; WO 99/06431; WO 99/06433; WO 99/06434; WO 99/06435; WO 99/06436; WO 99/06437; WO 98/54207; WO 99/10312; WO 99/10313; WO 98/53814; WO 98/53817; WO 98/58902). However, no potent and orally available small molecule inhibitors have been disclosed.
The neuropeptide receptors for substance P (neurokinin-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (Pernow, Pharmacol. Rev., 35:85-141, 1983). Substance P is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (Frederickson et al., Science 199:1359, 1978; Oehme et al., Science 208:305,1980) and plays a role in sensory transmission and pain perception (Jessell et al., Advan. Biochem. Psychopharmacol. 28:189, 1981). The usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Chrohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyperreflexia have been reported (Maggi et al., J. Auton. Pharmacol. 13:23-93, 1993; Snider et al., Chem. Ind. 1:792-794, 1991).
It has furthermore been suggested that tachykinin receptor antagonists have utility in the following disorders: anxiety, depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement of suppression such as systemic lupus erythmatosus (EPO Pub. No. 0,436,334), ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis (EPO Pub. No. 0,394,989).
The following documents relate to compounds that exhibit activity as neurokinin antagonists: U.S. Pat. No. 6,194,406 B1; U.S. Pat. No. 6,191,135 B1; U.S. Pat. No. 6,177,450 B1; U.S. Pat. No. 6,147,083; U.S. Pat. No. 6,114,315; U.S. Pat. No. 6,110,919; U.S. Pat. No. 6,063,926; U.S. Pat. No. 6,048,859; EPO Pub. No 1,099,446-A2; EPO Pub. No 1,110,958-A1; Published PCT WO200125219-A2; Published PCT WO200144200-A2.
While significant advances have been made in the synthesis and identification of conformationally constrained, reverse-turn mimetics, there is still a need in the art for small molecules that mimic the secondary structure of peptides. There is also a need in the art for libraries containing such members, particularly those small templates capable of supporting a high diversity of substituents. In addition, there is a need in the art for techniques for synthesizing these libraries and screening the library members against biological targets to identify bioactive library members. Further, there is a need in the art for small, orally available inhibitors of integrins, for use in treating inflammatory diseases and cardiovascular diseases, as well as some cancers. In particular there is a need for inhibitors of α4β1 and α4β7, for use in the treatment of rheumatoid arthritis, asthma, diabetes and inflammatory bowel disease. Further, there is a need in the art for small, orally available inhibitors of neurokinins, for use in treating inflammatory diseases, central nervous system disorders, as well as several other disorders. In particular there is a need for inhibitors of neurokinin-1, neurokinin-2, and neurokinin-3, for use in the treatment or prevention of various mammalian disease states, for example anxiety, asthma, cough, chronic obstructive pulmonary disease (COPD), bronchospasm, emesis, neurodegenerative disease, ocular disease, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, psychosis, and various gastrointestinal disorders such as Crohn's disease.
The present invention fulfills these needs and provides further related advantages.